The candidate for this mentored clinical scientist development award has a strong clinical interest in pulmonary hypertensive disorders and is committed to a research career in this field. The candidate's institution has a long, rich history of training distinguished clinical and basic scientists and provides an unparalleled environment for academic career development. The sponsor and co-sponsor are internationally acclaimed experts in the pathobiology of pulmonary hypertension (PH). The third member of the Advisory Committee is an expert in pulmonary endothelial cell biology and small G-protein signaling. The candidate will receive closely supervised research training, as well as a carefully selected program of didactic instruction. The research plan will test the hypothesis that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) attenuate pulmonary hypertension. Endothelial dysfunction is a key factor in the excessive vasoconstriction and abnormal vascular wall cell proliferation of severe PH. Statins have been shown to improve several normal endothelial cell functions, independent of their cholesterol lowering effect, through inhibition of small G-protein prenylation. The candidate has obtained preliminary data demonstrating that statins attenuate chronic hypoxic PH in rats. Specific aim #1 will test the ability of statins to attenuate PH and pulmonary vascular remodeling in a rat model of severe PH induced by chronic hypoxia plus vascular endothelial growth factor receptor-2 blockade. This model is characterized prominent endothelial as well smooth muscle cell proliferation, closely resembling human pulmonary arterial hypertension. Specific aim #2 will explore the cellular and molecular mechanisms responsible for the beneficial effect of statin treatment in this model. The long-term objectives of this research are to: 1) probe the cellular transduction mechanisms involved in the effects of statins, 2) to perform translational studies in humans with PH based on these concepts and ultimately, 3) to develop novel therapies for this life-threatening disorder. This award will allow the candidate to develop into a well-trained independent researcher in PH.